CEACAM3 - CEA cell adhesion molecule 3 |Elisa - Clia - Antibody - Protein

Background

CEACAM3, also known as CD66d, is part of the carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), a subgroup within the immunoglobulin superfamily (IgSF). CEACAM3 is primarily expressed on granulocytes, particularly neutrophils, and plays a crucial role in the innate immune response, specifically in defending against bacterial infections. Unlike other CEACAM family members that are primarily involved in cell-cell adhesion and tumor biology, CEACAM3 is highly specialized for recognizing and mediating the phagocytosis of bacteria, particularly pathogenic Neisseria species, Haemophilus influenzae, and Moraxella catarrhalis.

CEACAM3 functions as an opsonin-independent phagocytic receptor, enabling neutrophils to directly recognize and engulf bacteria without the need for antibody or complement opsonization. This receptor is a critical component of the host defense system against specific bacterial pathogens that have evolved to exploit CEACAM family proteins to adhere to host cells.

Protein Structure

The structure of CEACAM3 is central to its function in bacterial recognition and phagocytosis. It is a single-pass transmembrane protein composed of several distinct regions:

Extracellular Domain:

• The extracellular region of CEACAM3 contains a single immunoglobulin variable (IgV)-like domain. This domain is responsible for binding bacteria, specifically those that express certain outer membrane proteins that engage with CEACAM3.
• The IgV-like domain facilitates interactions with bacteria by recognizing conserved motifs on the bacterial surface, particularly pili or other adhesion molecules, allowing CEACAM3 to mediate direct binding and subsequent phagocytosis.

Transmembrane Domain:

• CEACAM3 spans the plasma membrane with a typical hydrophobic transmembrane domain, anchoring it into the neutrophil’s membrane. This region is not involved in signaling directly but plays a structural role by maintaining the receptor’s position in the membrane.

Cytoplasmic Domain:

• The cytoplasmic tail of CEACAM3 contains a critical immunoreceptor tyrosine-based activation motif (ITAM)-like sequence. Upon bacterial binding, the ITAM-like domain is phosphorylated by Src family kinases, initiating a signaling cascade that leads to actin cytoskeleton rearrangement and the engulfment of the pathogen through phagocytosis.
• This signaling cascade involves the recruitment of various intracellular proteins, such as Syk (spleen tyrosine kinase), and triggers the assembly of the phagocytic machinery in neutrophils. This direct signaling pathway is essential for the opsonin-independent engulfment of bacteria.

Glycosylation:

• Like other CEACAM family members, CEACAM3 is glycosylated, which contributes to its stability and potentially modulates its interactions with bacterial ligands. Glycosylation sites in the extracellular domain can influence its adhesion properties, although they are not the primary determinants of its bacterial recognition function.

Classification and Subtypes

CEACAM3 is a distinct member of the CEACAM family, which includes other well-characterized members such as CEACAM1, CEACAM5 (CEA), and CEACAM6. Unlike these family members, which have roles in cell adhesion, immune modulation, and tumor progression, CEACAM3 is uniquely adapted to function in the innate immune system.

• CEACAM1: Primarily involved in cell-cell adhesion, immune regulation, and tumor suppression.
• CEACAM5 (CEA): Known for its role as a tumor marker and involvement in cancer progression.
• CEACAM6: Involved in tumorigenesis and immune evasion by pathogens.

CEACAM3 does not have subtypes, but its expression is specifically upregulated in neutrophils and plays a specialized role in bacterial phagocytosis. Its function is distinct from other CEACAM family members, which are more broadly expressed across epithelial and immune cells.

Function and Biological Significance

CEACAM3’s primary biological function is its role in the innate immune response to bacterial infections. It acts as a pattern recognition receptor that directly binds bacteria, facilitating their internalization and destruction by neutrophils. This function is crucial in the early immune response, where rapid clearance of pathogens is required to prevent infection spread.

Bacterial Phagocytosis:

• CEACAM3 is specialized for the phagocytosis of Gram-negative bacteria, particularly species that express CEACAM-binding proteins, such as Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus influenzae, and Moraxella catarrhalis. Upon bacterial binding to the CEACAM3 extracellular domain, the receptor’s cytoplasmic ITAM-like motif becomes phosphorylated, triggering phagocytic signaling cascades.
• This opsonin-independent pathway allows for the rapid engulfment of bacteria without requiring prior antibody or complement deposition, a process that is particularly important during the early stages of bacterial invasion when adaptive immune responses have not yet been mounted.

Immune Response Modulation:

• CEACAM3 not only facilitates bacterial phagocytosis but also contributes to the modulation of neutrophil activity during infection. Upon activation, CEACAM3 induces signaling pathways that lead to the production of reactive oxygen species (ROS) and other antimicrobial agents, enhancing the ability of neutrophils to kill engulfed bacteria.
• CEACAM3-mediated phagocytosis also promotes the secretion of pro-inflammatory cytokines, which help to recruit additional immune cells to the site of infection and enhance the overall immune response.

Pathogen Evasion Mechanisms:

• Interestingly, some bacterial pathogens have evolved to exploit CEACAM family members, including CEACAM3, for immune evasion. Certain bacteria can bind to CEACAM receptors to adhere to host cells and avoid immune detection. However, CEACAM3 has evolved to counteract this evasion by directly mediating bacterial clearance through phagocytosis, highlighting its importance in host defense.

Clinical Issues

Infectious Diseases:

• CEACAM3 plays a key role in the clearance of pathogenic bacteria, particularly those that cause mucosal infections, such as gonorrhea, meningitis, and respiratory tract infections. Mutations or deficiencies in CEACAM3 may impair neutrophil function, leading to increased susceptibility to infections by these pathogens.
• Since CEACAM3 specifically mediates opsonin-independent phagocytosis, any disruption in its function could result in a failure to effectively clear bacteria in the early stages of infection, potentially leading to more severe or chronic infections.

Cancer:

• While CEACAM3’s primary function is in innate immunity, aberrant expression of CEACAM family members, including CEACAM3, has been observed in certain cancers. However, CEACAM3 itself is not as commonly associated with tumorigenesis as other CEACAM family members like CEACAM5 or CEACAM6. Nonetheless, its expression in immune cells could potentially influence the tumor microenvironment, particularly in modulating neutrophil responses to tumor-associated inflammation.

Therapeutic Targeting:

• Targeting CEACAM3 or its downstream signaling pathways could potentially be explored as a therapeutic strategy to enhance neutrophil responses in bacterial infections. Additionally, manipulating CEACAM3 expression or function may help improve outcomes in conditions where neutrophil function is compromised, such as in chronic granulomatous disease (CGD), where neutrophils are unable to produce sufficient ROS to kill phagocytosed pathogens.

Summary

CEACAM3 (CD66d) is a critical receptor in the innate immune response, specifically mediating the opsonin-independent phagocytosis of pathogenic bacteria by neutrophils. Structurally, it consists of an IgV-like extracellular domain that binds bacteria, a transmembrane domain, and a cytoplasmic ITAM-like motif that triggers phagocytic signaling cascades. This receptor is highly specialized for recognizing bacteria such as Neisseria and Haemophilus species, facilitating their rapid clearance by neutrophils.

Functionally, CEACAM3 plays a central role in the immune system’s ability to combat bacterial infections, particularly in mucosal tissues. It promotes both the phagocytosis and destruction of bacteria while also modulating neutrophil activity through the production of ROS and pro-inflammatory signals.

Clinically, CEACAM3 is important in the context of infectious diseases caused by bacteria that exploit CEACAM receptors. Understanding its function in immune responses could lead to improved therapeutic strategies for treating bacterial infections, particularly in individuals with impaired neutrophil function or in cases of bacterial immune evasion. CEACAM3 represents a vital component of the host defense system, with its ability to mediate rapid, opsonin-independent bacterial clearance.